Genetics of Dentofacial and Orthodontic Abnormalities

Published online: 2021-02-01 THIEME Review Article 95

Praveen Kumar Neela1 Anjana Atteeri1 Pavan Kumar Mamillapalli1 Vasu Murthy Sesham1 Sreekanth Keesara1 Jaya Chandra1 Udayini Monica1 Vasavi Mohan2

1 Department of Orthodontics, Kamineni Institute of Dental Sciences, Address for correspondence Praveen Kumar Neela, BDS, MDS, DIBO, Narketpally, India M(Orth) RCPS (Glasg), Department of Orthodontics, Kamineni 2 Department of Genetics and Molecular Medicine, Vasavi Medical and Institute of Dental Sciences, Narketpally 508254, Telengana, India Research Centre, Hyderabad, Telangana, India (e-mail: [email protected]).

Global Med Genet 2020;7:95–100.

Abstract The development of craniofacial complex and dental structures is a complex and delicate process guided by specific genetic mechanisms. Genetic and environmental factors can influence the execution of these mechanisms and result in abnormalities. An insight into the mechanisms and genes involved in the development of orofacial and dental structures has gradually gained by pedigree analysis of families and twin studies as well as experimental studies on vertebrate models. The development of novel Keywords treatment techniques depends on in-depth knowledge of the various molecular or ► genetics cellular processes and genes involved in the development of the orofacial complex. This ► genes review article focuses on the role of genes in the development of nonsyndromic ► polymorphism orofacial, dentofacial variations, malocclusions, excluding cleft lip palate, and the ► dentofacial variations advancements in the field of molecular genetics and its application to obtain better ► malocclusion treatment outcomes.

Introduction Understanding the genetic factors contributing to the variation in dentofacial morphology associated with mal- Genetics as an etiological factor plays a crucial role in the occlusions is the key for proper diagnosis which, in turn, development of jaws, both maxilla, and mandible, denti- helps to develop novel treatment techniques. Advances in tion, and occlusion. In 1836, Frederick Kussel reported that dentofacial phenotyping, which is the comprehensive char- malocclusion, both skeletal and dental, could be transmitted acterization of hard- and soft-tissue variation in the cra- from one generation to another and also stated that chro- niofacial complex, together with the acquisition of large- mosomal defects account for approximately 10% of all scale genomic data have started to unravel genetic mech- malocclusions.1 The pioneering work of Gregor Johann anisms underlying facial variation. Knowledge of the ge- Mendel initiated an interest in the field of genetics in the netics of human malocclusion is limited even though 19th century, and since then, genetics has been an essential results attained thus far are encouraging, with promising part of the studies performed in various fields of biological opportunities for future research.3 This review article and medical sciences. Since the 20th century, this branch of summarizes the role of genes in the development of non- science has evolved through a series of era-based concep- syndromic orthodontic, dentofacial variations, excluding tual breakthroughs. Lack of sufficient understanding of clefts, malocclusions, and the advancements in the field principles of inheritance in the past led to a view regarding of molecular genetics and its application to obtain better genetics and malocclusion remaining unclear.2 treatment outcomes.

published online DOI https://doi.org/ © 2021. The Author(s). February 1, 2021 10.1055/s-0040-1722303. This is an open access article published by Thieme under the terms of the ISSN 2699-9404. Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/) Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany 96 Genetics of Dentofacial and Orthodontic Abnormalities Neela et al.

Genetic Influence on Skeletal Relationship of mandibular size.20 Savoye et al also reported similar findings Jaws and stated that the vertical proportions are highly under genetic control.21 Mandibular prognathism is caused by a deficiency of the maxillary growth, excessive mandibular growth, or a combi- Genetic Effects on Individual Tooth nation of both. Familial studies of mandibular prognathism Variations are suggestive of heredity in the etiology of this condition. Various models have been suggested, such as autosomal Genetic factors control the tooth size, morphology, number, dominant with incomplete penetrance, simple recessive, position, and its inheritance, as stated in various twin – variable both in expressivity and penetrance with differences studies.22 24 HOX genes, which play a fundamental role in in different racial populations.4 The familial nature of man- the oral and dental development, are known to show site- dibular prognathism was first reported by Strohmayer as specific anteroposterior expression patterns. Molecular ge- noted by Wolff et al. in their analysis of the pedigree of the netics of tooth morphogenesis, with the homeostatic Hox 7 Habsburg family.5 The Habsburg jaw is seen in European and Hox 8 (presently MSX1 and MSX2) genes being respon- royalty in which mandibular prognathism recurred over sible for stability in dental patterning, is confirmation of multiple generations. The genetic factors appear to be het- Butler’s field theory.25 erogeneous with monogenic influence (usually autosomal A supernumerary tooth, which is most frequently seen in dominant with incomplete penetrance and variable expres- the premaxillary region with a greater prevalence for males, sivity) in some families and multifactorial (polygenic com- also appears to be genetically determined. Niswander and plex) influence in others.6 Sujaku26 in 1963 analyzed data from family studies, and they Although various genetic linkage analyses and genome- suggested that, like hypodontia, the genetics of less prevalent wide association studies have identified many genes and loci condition of supernumerary teeth is under control of several associated with mandibular prognathism, the genes under- genes in different loci and may be associated with an lying the risk of mandibular prognathism in the general autosomal recessive gene with lesser penetrance in females. population remain ambiguous, leaving some impetus to This was later supported by Galas and Garcia in 1999.27 search for new candidate genes. To date, genome-wide While an autosomal dominant inheritance with incomplete linkage analyses of mandibular prognathism have been penetrance has been suggested, the increased incidence in performed among Japanese, Korean, Hispanic, and Chinese males suggests the possibility of sex-linked heredity, as

cohorts and several genetic loci have been reported to be stated by Bruning et al. Although this inheritance does not associated with it, including 1p22.1, 1q32.2, 1p36,3q26.2, follow a simple Mendelian pattern, these are more common- 4p16.1, 6q25, 11q22, 12q13.13, 12q23, 14q24.3–31.2, and ly present in parents and siblings of patients who present – 19p13.2.7 13 Genome-wide linkage and association studies with this condition. Evidence from twins with supernumer- also found positive correlations for mandibular prognathism ary teeth also supports this theory.28 and genes, growth hormone receptor (GHR),14 erythrocyte Dental agenesis, which is the most common developmen- membrane protein band4.1 (EPB4),15 synovial sarcoma X tal anomaly seen in humans, is genetically and phenotypi- (SSX21), myosin1H (MYO1H),16 collagen type II α1 cally a heterogeneous condition. Based on the current (COL2A1),17 fibroblast growth factor (FGF7),18 transforming knowledge of genes and the factors involved in the tooth growth factor beta 3 (TGFB3), plexin A (PLXNA), latent development and morphogenesis, it is assumed that differ- transforming beta binding protein 2 (LTBP2), matrilin1 ent phenotypic forms are caused by different genes involving (MATN1),9 dual specificity phosphatase 6 (DUSP6),11 and a different interacting molecular pathways, providing an ex- disintegrin and metalloproteinase with thrombospondin planation not only for the wide variety in agenesis patterns motifs 1 (ADAMTS1)13 in various populations. but also for associations of dental agenesis with other oral anomalies. More than 200 genes have so far been identified, Vertical Skeletal Jaw Abnormalities which are expressed during tooth development, and mutations in several of these genes are known to cause arrested Fontoura et al in their study suggested two candidate genes, tooth development in mice.29 PAX5, a transcription factor, and Rho GTPase activating Population studies have shown that tooth agenesis can be protein 29 (ARHGAP29), which mediates the cyclical regula- manifested as an isolated trait or part of a syndrome. Isolated tion of small GTP binding proteins such as RhoA, are associ- forms may be either sporadic or familial. Familial tooth ated with the vertical discrepancies, ranging from skeletal agenesis can be the result of a single dominant gene defect deep bite to open bite.19 Manfredi et al in a more recent study or recessive or X-linked. Third molar agenesis cannot be on monozygotic twins, dizygotic twins, and same-sex sib- explained in most of the cases with a simple model of autoso- lings, assessed the inheritance traits of the orthodontic mal dominant transmission. Besides, a polygenic mode of cephalometric parameters. They also suggested that the inheritance has also been reported in the literature. Grahnen30 vertical parameters were more genetically controlled than stated that tooth agenesis is typically transmitted as an the anteroposterior ones; heritability seemed to be autosomal dominant trait with incomplete penetrance and expressed more anteriorly than posteriorly. The mandibular variable expressivity. Twin studies have been widely used to shape seemed to be determined more genetically than the show the importance of the genetic component involved

Global Medical Genetics Vol. 7 No. 4/2020 © 2021. The Author(s). Genetics of Dentofacial and Orthodontic Abnormalities Neela et al. 97 during tooth development to control both tooth size and form. this association study was done in the Hong Kong Chinese There are numerous case reports, suggesting concordance for population, the results might not apply to other ethnic tooth agenesis in monozygotic twins, and case reports where groups. Further replication studies in other ethnic groups variation in the expressivity is observed.31 with a larger sample size are vital for confirmation of these Numerous mutations in transcription factor and growth findings.35 factor-related genes involved in dental development have A genetic tendency for ectopic maxillary canines has also been shown to play a role in human dental agenesis, includ- been reported in various association studies.36 Peck et al ing paired box 9 (PAX9), a transcription factor, and muscle concluded that palatally ectopic canines, as an inherited trait, segment homeobox 1 (MSX1). MSX1 gene mutations can is one of the anomalies in a complex of genetically related lead to hypodontia or oligodontia as well as variations in the dental disturbances, often occurring in combination with downstream signaling gene bone morphogenetic protein 4 missing teeth, tooth size reduction, supernumerary teeth, (BMP4). In humans, a point mutation in MSX1 homeobox and other ectopically positioned teeth.37 Previous studies results in agenesis of second premolars and third molars in have also shown an association between ectopic maxillary affected individuals.25 canines and class II division 2 malocclusion, a genetically Mutations in PAX9 typically show a nonsyndromic auto- inherited trait.38 somal dominant mode of inheritance for oligodontia, with Genetic variation showing a significant effect on arch variable expressivity within families. The characteristic width and length was confirmed in various studies on pattern of dental agenesis caused by PAX9 mutations pri- monozygotic and dizygotic twins. A genetic contribution to marily affects molars in both dental arches and second arch shape was found by Richards et al after comparing the premolars most often in the maxillary arch than the man- intraclass correlations between monozygotic and dizygotic dibular arch, occasionally presenting with missing or peg- South Australian twins.39 shaped mandibular central incisors and maxillary lateral A study was conducted by Corruccini et al on the occlusal incisors. Agenesis of maxillary first premolars or canines characteristics in 32 pairs of monozygotic twins and 28 pairs can occur with a low frequency among PAX9 mutations. In of dizygotic twins using dental stone casts. They studied arch contrast, the PAX9 Ala240Pro mutation may be unique, in shape, size, and symmetry, overjet, overbite, posterior cross- that it leads uniquely to third molar agenesis with or bite, buccal segment relation, rotation, and displacements. without affected incisors. Mutations in the axis inhibitor They concluded that arch size variation, tooth displacement, 2 gene (AXIN2) have also been linked to oligodontia, often and crossbite showed significant genetic variance and also exhibiting a similar pattern of affected teeth as PAX9 found an increased environmental component of variance in mutations.32 From this, it is clear that the functions of occlusion.40 A study on north-west Indian twins revealed PAX9 and MSX1 are essential for the establishment of the significant genetic variance for dental arch and palate dimen- odontogenic potential of the mesenchyme through the sions, but environmental influences seemed important for maintenance of mesenchymal Bmp4 expression. However, occlusal traits.41 the relationship between these three genes on the molecular level remains unknown. Effects of Genetics on Inheritance of Primary failure of eruption (PFE), which was described Malocclusion initially by Profitt and Vig,33 is characterized by nonsyndromic eruption failure of permanent teeth in the absence Malocclusion is a significant deviation from an ideal or of mechanical obstruction. Many studies have stated the normal occlusion.38 Malocclusion can either be skeletal or heritable basis of this dental phenotype, and recently, dental, involving discrepancies in the jaw size, tooth size, mutations in parathyroid hormone receptor 1 (PTH1R) and shape, crowding, or spacing. It is a manifestation of have been identified. It functions in signaling in mesenchy- both genetic factors and environmental influences during mal progenitors, alveolar bone formation, and periodontal the development of the craniofacial complex. However, it ligament development during eruption physiology. The might be difficult to differentiate whether the malocclu- recent report of PTH1R mutations associated with primary sions are determined by the genetic code or environmental failure of eruption makes this a high-priority candidate factors, or a combination of both.42 The concepts and gene for confirming the diagnosis of a nonsyndromic PFE principles of molecular genetics have become significant phenotype.34 components in the understanding of the genesis of varia- Crowding of teeth is a complex dental anomaly that tions in the growth, development, and form of the entire affects esthetics and quality of life. Crowding is usually craniofacial complex. caused by insufficient arch space that cannot accommodate Genetic factors playing a predominant role in the etiology all erupting permanent teeth. Genetics is suggested to con- of malocclusion is backed by population studies, especially tribute to the etiology of crowding. A study conducted by family and twin studies.43 Familial aggregation studies sug- Ting et al suggested a significant association for the genes gested that an autosomal dominant model with incomplete ectodysplasin A (EDA) and X-linked ectodermal dysplasia penetrance has the most significant validity for Class III receptor (XEDAR), which are important in the signaling pedigrees, including the royal Habsburg family5 and others pathway that plays a role in the development of dental from middle Eastern,44 South American,16,45 and Eastern crowding among the Hong Kong Chinese population. Since European descent. In contrast, polygenic inheritance and

autosomal dominance models, with incomplete penetrance found that patients who were homozygous for IL-1B allele 1 and variable expressivity, have been suggested for Class II have a 5.6 fold (95% CI 1.9–21.2) increased risk of apical root division 1 and 2, respectively.46 Lauweryns in 1993 reported resorption (ARR) compared with those who were not homo- that 40% of the dental and skeletal variations that lead to zygous for the IL-1B allele.57 Another candidate locus identi- malocclusion could be attributed to genetic factors.47 fied to be associated with the development of ARR is located Extensive cephalometric studies by Harris suggested the on chromosome 18 and showed evidence for linkage be- concept of polygenic inheritance for Class II division 1 tween a microsatellite marker D18S64, which lies close to the malocclusion, showing that the craniofacial skeletal patterns candidate gene TNF receptor superfamily member 11a of children with class II malocclusions are heritable and that (TNFRSF11A) and root resorption trait. The TNFRSF11A there is a high resemblance to the skeletal patterns in their gene encodes the receptor activator of nuclear factor-kappa siblings with normal occlusion.48 B (RANK), an essential signaling molecule in osteoclast Familial occurrence of Class II division 2 has been docu- formation and activation as a potential mechanism in the mented in several published reports including twin and pathogenesis of root resorption.58 triplet studies (Kloeppel; Markovic) and family pedigrees 49 50 from Korkhaus, Rubbrecht, Trauner, and Peck et al. Twin Genetic Implications on Orthodontic Tooth studies showed that the identical twins demonstrated 100% Movement concordance for Class II division 2 malocclusion, indicating a strong genetic influence in the development of Class II Multiple molecular pathways that influence orthodontic tooth division 2 deep bite malocclusions.51 Markovic’s clinical and movement (OTM) are identified to date. Two of the pathways cephalometric study of intra- and interpair comparisons of that influence both orthodontic tooth movement and external 114 Class II division 2 malocclusions, 48 twin pairs, and six apical root resorption include the ATP/P2XR7/IL-1B inflam- sets of triplets showed complete penetrance and variable matory signaling pathway and the RANKL/RANK/OPG bone expressivity of autosomal dominant genetic impression.52 modelling and remodeling pathway. However, even with this The controversy regarding the etiology of the Class II knowledge of key pathways influencing OTM, few studies have Division 2 malocclusion arises from a failure to appreciate focused on determining how actual variations in nonsyn- the synergistic effects of genetics and the environment on dromic genetic factors correlate with the actual clinical out- facial morphology. Ballard, Houston, Mills,53 and others comes observed during OTM in humans.59 Studies have been considered that a high lip line and a particular lip morphol- done with genetic variation markers based on the part of the

ogy and behavior were the main etiological factors. Graber, ATP/P2RX7/ IL-1B pathway, the genes for IL-1β and another Hotz, Meskov and Markovic54 stressed the predominant role related cytokine interleukin 1 α IL-1α (IL1B and IL1A, respec- of genetic factors in the etiology of Class II division 2 tively), and the gene (IL1RN) for another molecular pathway malocclusions. (IL-1 receptor antagonist, IL-RA) that helps to regulate their Nakashima et al.55 conducted a study to assess the role of biological activity.60 Of these two forms, interleukin 1 β-IL-1β heredity in the development of Angle’s Class II and Class Ill is the most potent for bone resorption and inhibition of bone malocclusions, and their results showed that: 1) The parents formation. OTM requires a balance between IL-1β and IL-1RA of Class II patients had a convex profile with a distocclusion synthesis for the bone modelling and remodeling processes type of denture pattern, while the parents of Class III patients involved.61 had a concave profile with a mesiocclusion type of denture pattern, suggesting both Class II and Class III malocclusions Conclusion have a genetic basis. These correlations between parent and offspring were stronger for the skeletal measurements in The knowledge of the role of genetics is essential for the both classes. 2) The correlation coefficients in the parent- orthodontist which helps to understand why a patient has a offspring data were in good agreement with the expected particular occlusion, because malocclusion is a manifesta- level under the polygenic model of inheritance. 3) Significant tion of genetic and environmental interaction on the devel- differences between Class II and III patients for four variables opment of the orofacial complex. Awareness regarding the (upper incisor to NA angle, gonial angle, Ar-Go, and upper genetic expression of the dentofacial maldevelopment is an incisor to nasal floor angle) were considered to be related to essential aid in the correction of malocclusion, as it helps to environmental factors.55 segregate the inherited malocclusions from those due to the effect of environmental factors and thereby helps to diag- Genetic Effects on External Apical Root nose, treat, and possibly even prevent a malocclusion from Resorption occurring in the next generation. There has been immense progress in the field of geneti- Evidence from previous studies suggest that genetic factors cally supported orthodontics to date. Although it is very play a significant role in the development of root resorp- challenging to reveal the genetic component of most tion.56 Al-Qawasmi and colleagues in 2003 performed a malocclusions and dental anomalies because of its poly- family study to assess the potential effect of single nucleotide genic nature, data developed and provided by the human polymorphisms (SNPs) in two closely-located proinflamma- genome project have made it feasible to map inherited tory candidate genes (IL-1A and IL-B) on root resorption and conditions related to the dentofacial development.

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